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Hallmarks of Aging: Genomic Instability

This is the first of a series of mini-primers on the “9 Hallmarks of Aging”

Aubrey de Gray is one of  the trailblazers reshaping how we think about longevity and how to reverse aging. One of his big contributions was to reframe how we look at aging as a “maintenance” problem in our bodies due to a series of processes that accumulate damage at the cellular level, causing us to age. These processes became known as the “hallmarks of aging.”  

Understanding what these hallmarks are at a high level can help you start thinking differently about your personal longevity protocol and the practices it should  include.

Hallmark #1: Genome instability

Genome instability is considered to be one of the key factors that drive aging. 

It is caused by DNA damage that accumulates over time and disrupts the normal functioning of our organism at a cellular level. This in turn can give rise to age-related diseases such as cancer.

DNA damage can be classified into two types: 

(1) DNA transcription errors that normally occur either during the replication of cells or in the process of repairing damaged cells (i.e., DNA mutations); and 

(2) DNA damage that involves the physical alteration of cellular structures due to a broad variety of factors (e.g., oxidative stress).

DNA stability can also be threatened by exogenous factors. These are stressors in the environment fromphysical, chemical, and biological agents. Examples of these includeUV rays, radiation, chemicals, tobacco, and alcohol.

Process of genomic instability

Cell. 2013 Jun 6; 153(6): 1194–1217.

Luckily, we have evolved a complex network of DNA repair mechanisms that is able to repair most of the naturally occurring damage. Certain enzymes, for instance, can detect broken strands of DNA and attempt to reverse the alterations. 

If a cell is damaged and cannot be repaired, there are also mechanisms that can trigger cell death or block further replication of the damaged cell (respectivelyapoptosis and senescence).

DNA damage repair mechanisms

Cell. 2013 Jun 6; 153(6): 1194–1217.

But, none of these built-in repair systems is perfect. Errors can occur in the process of repairing damaged cells, which can then replicate their DNA containing such errors. Mistakes can also occur during the replication of chromosomes in the regular process of cell division. 

The cumulative damage can ultimately disrupt the normal cell cycle, change gene expressions, and interfere with gene regulation. It is thought that this ultimately explains age-related cellular degeneration and functional decay. The outcome of this process is the development of cancer and other degenerative diseases.

The causal relationship between this genomic instability and aging has been clearly established in a number of studies using animal models (e.g., mice). Cumulative DNA damage has also been identified as the underlying cause of several syndromes that cause accelerated aging in humans (i.e.,Progeroid syndromes

It is believed that our DNA repair capacity may decrease with age. Markers of DNA damage have been observed in many age-associated diseases including cardiovascular disease, cancer, and dementia. This has led scientists to conclude that genome instability could be a causal factor of these types of diseases. 

What can be done

With the growing understanding of the connection between cumulative DNA damage and many age-related diseases, interventions targeting DNA repair is a major focus in the development of anti-aging medicines.

While there are many promising developments, full-fledged solutions to cumulative DNA damage are years away. In the meantime, there are a number of potentially helpful strategies that you can try today that may be helpful.

Minimizing damage: 

  • One way to try to reduce the amount of DNA damage is through the use of antioxidants such as vitamin C and E, as well as glutathione. These are thought to protect the genome by counteracting oxidative stress 
  • The use of aspirin has been suggested to stimulate repair of certain types of DNA damage (nucleotide excision repair). Aspirin has also been shown to increase the lifespan of mice. However, the mechanism by which this happens has not been fully understood

Boost mitochondrial health:

Themitochondria are an essential part of each cell. They generate the energy that a cell needs to function normally and are also subject to DNA damage (mitochondria have their own DNA).

When mitochondria become dysfunctional, they not only produce less energy but they also start to generate excessive levels of reactive oxygen species, which in turn leads to oxidative stress and, ultimately, cell damage.

As a result, much focus has been placed on these organelles as a key to healthy aging.

  • Exercisehas been demonstrated to have a powerful impact on both mitochondrial health and density in muscle tissue. 
  • There is alsogrowing evidence that increasing NAD+ levels through supplementation may help boost mitochondrial health. Boosting levels can ensure the availability of energy as well as the proper function of many metabolic processes. NAD+ is a coenzyme found in every cell in our bodies, but it is now known that NAD+ levels decline with age.
  • Having adequate levels of cellular NAD+ is also critical to activate a set of proteins called sirtuins. Multiplesirtuins appear to play an important role in regulating the rate of aging in a number of species. Additionally, most mammalian sirtuins stimulate DNA repair.

Boost ketone levels through diet, intermittent fasting or with exogenous ketones

  • There is a growing body of evidence that points to the fact that ketone bodies, when used as an energy source, can have an attenuating effect on the rate of aging. In particular, a ketone named beta-hydroxy-butyrate (BHB) has been shown to have protective effects against brain aging
  • Ketones are naturally produced by the liver and their levels can be significantly increased by following a high-fat diet (keto) or through intermittent fasting.

Boost clearance of damaged cells

  • Looking downstream, when DNA damage cannot be repaired, it is important to remove the damaged cells. This is a process known asautophagy by which we get rid of dysfunctional cells.Spermidine is a naturally occurring compound in wheat that has been shown to help regulate the process of autophagy.
  • Another mechanism we use to neutralize damaged cells issenescence. Senescent cells don’t replicate, but they also don’t die, accumulating over time. This can trigger a cascade of potentially harmful chemical signaling that encourages nearby cells to also become senescent, aprocess that has beenshown to have a causal link with aging. Natural compounds like Fisetinhave been shown to help eliminate senescent cells in mice and human tissue. 

DNA Repair Strategies

Cell. 2013 Jun 6; 153(6): 1194–1217.

n short, you are never too young—or too old—to actively seek to limit the damage and boost the repair of our cells in order to limit the effects of aging. And, there are several real and no-to-low risk actions we can take today to get started.

Resources to go deeper

The Hallmarks of Aging

Genome instability and aging: Cause or effect?

Protecting the Aging Genome



 

 

 

 

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